West Nile Virus–associated Flaccid Paralysis

Sejvar, James J.; Bode, Amy V.; Marfin, Anthony A.; Campbell, Grant L.; Ewing, D J; Mazowiecki, Michael; Pavot, Pierre V.; Schmitt, Joseph M.; Pape, John; Biggerstaff, Brad J.; Petersen, Lyle R.

doi:10.3201/eid1107.040991

Cited by 165 publications

(169 citation statements)

References 26 publications

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“…Two unique features are associated with WNV-induced acute flaccid paralysis: it can occur as an isolated disease in the absence of meningitis or encephalitis (34), and patients of all ages and immune status groups are at risk (12). Our experiments suggest that the route of WNV entry into the CNS in part determines pathological outcome.…”

Section: Discussionmentioning

confidence: 77%

Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysis

Samuel

Wang

Siddharthan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

195

176

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West Nile virus (WNV) has emerged as a significant cause of epidemic viral encephalitis and flaccid limb paralysis, yet the mechanism by which it enters the CNS remains uncertain. We used compartmentalized neuron cultures to demonstrate that WNV spreads in both retrograde and anterograde directions via axonal transport. Transneuronal spread of WNV required axonal release of viral particles and was blocked by addition of a therapeutic neutralizing antibody. To test the physiologic significance of axonal transport in vivo, we directly inoculated the sciatic nerve of hamsters with WNV. Intrasciatic infection resulted in paralysis of the hind limb ipsilateral but not contralateral to the injection site. Limb paralysis was blocked either by surgical transection of the sciatic nerve or treatment with the therapeutic neutralizing antibody. Collectively, these studies establish that WNV undergoes bidirectional spread in neurons and that axonal transport promotes viral entry into the CNS and acute limb paralysis. Moreover, antibody therapeutics directly inhibit transneuronal spread of WNV infection and prevent the development of paralysis in vivo.flavivirus ͉ neuron ͉ retrograde ͉ transneuronal spread W est Nile virus (WNV) is a neurotropic member of the Flaviviridae family of RNA viruses and is related to other important arthropod-borne human pathogens. WNV is maintained in an enzootic cycle between mosquitoes and birds and has become an important global cause of epidemic encephalitis. Since its emergence in the United States in 1999, Ϸ26,000 cases of symptomatic WNV infection have been confirmed (www.cdc. gov/ncidod/dvbid/westnile/surv&control.htm#maps), and seroprevalence studies suggest that several million people have been infected (1).Rodent models have provided insight into the mechanisms of WNV spread to the CNS. After s.c. inoculation, WNV-infected dendritic cells traffic to the draining lymph node, resulting in a primary viremia and infection of peripheral tissues. Within 6 days, WNV is cleared from the serum and peripheral organs and enters the CNS and induces neurological disease (reviewed in ref.2). Nonetheless, the specific mechanisms by which WNV or other neurotropic flaviviruses enter into the CNS are largely unknown. CNS infection may occur in part via hematogenous spread, as increased viremia in immunodeficient mice (2) and TNF-␣-mediated changes in blood-brain-barrier permeability correlate with earlier CNS entry (3).Axonal transport from infected peripheral neurons mediates CNS entry and pathogenesis of viruses in the Herpesviridae, Rhabdoviridae, and Picornaviridae families (4-6). Viral spread in neurons is generally mediated by fast axonal transport, a microtubule-associated, anterograde and retrograde transport system. In classical studies, CNS infection of rabies virus or poliovirus was prevented by axonal ligation or degeneration (7,8). Insights into the biology of axonal spread have been facilitated by the development of compartmentalized, or Campenot, chambers for culturing neurons (9). These s...

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Section: Discussionmentioning

confidence: 77%

Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysis

Samuel

Wang

Siddharthan

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

195

176

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“…27 Other distinctive findings include cranial neuropathies (in 20% of patients with WNV meningoencephalitis)-most commonly unilateral or bilateral peripheral facial palsywhich might have a delayed onset in the second or third week following onset of illness. 5,[27][28][29][30] Movement disorders (dyskinesias) are common in patients with WNV meningoencephalitis, and can include postural or kinetic tremor (in up to 90% of patients), parkinsonism (including cogwheel rigidity, bradykinesia and postural instability [70%]), and myoclonus (20-40%). 26 AFP can occur in isolation, or in combination with meningitis or meningoencephalitis.…”

Section: Clinical Featuresmentioning

confidence: 99%

“…7 Neuroinvasive presentations (Box 1) are varied and include aseptic meningitis, meningoencephalitis and AFP syndrome (a poliomyelitis-like illness). 5,[26][27][28][29][30] Brainstem encephalitis, cerebellitis, movement disorders, cranial neuropathies, polyneuropathy/radiculopathy, chorioretinitis and optic neuritis are also recognized WNV neurological presentations. The proportion of neuroinvasive disease manifesting as meningitis, as opposed to encephalitis or myelitis, has varied greatly within a given epidemic season and locale.…”

Section: Clinical Featuresmentioning

confidence: 99%

“…26 AFP can occur in isolation, or in combination with meningitis or meningoencephalitis. 27 The relative frequency of pure AFP compared with AFP in combination with meningoencephalitis is uncertain, but might be as high as 50%. 5 Unlike meningoencephalitis, the WNV AFP syndrome does not predominantly affect the elderly, but has been reported in all age groups.…”

Section: Clinical Featuresmentioning

confidence: 99%

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West Nile virus meningoencephalitis

2006

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SUMMARYSince its first appearance in the US in 1999, West Nile virus (WNV) has emerged as the most common cause of epidemic meningoencephalitis in North America. In the 6 years following the 1999 outbreak, the geographic range and burden of the disease in birds, mosquitoes and humans has greatly expanded to include the 48 contiguous US and 7 Canadian provinces, as well as Mexico, the Caribbean islands and Colombia. WNV has shown an increasing propensity for neuroinvasive disease over the past decade, with varied presentations including meningitis, encephalitis and acute flaccid paralysis. Although neuroinvasive disease occurs in less than 1% of infected individuals, it is associated with high mortality. From 1999-2005, more than 8,000 cases of neuroinvasive WNV disease were reported in the US, resulting in over 780 deaths. In this review, we discuss epidemiology, risk factors, clinical features, diagnosis and prognosis of WNV meningoencephalitis, along with potential treatments.

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“…WNV can infect and cause a broad spectrum of disease severity, ranging from fever to encephalitis and flaccid paralysis in both animals and humans (Hayes et al, 2005b;Sejvar et al, 2005). The WNV genome comprises 11 kb positive-stranded RNA that is translated into a viral polyprotein and processed by viral and cellular enzymes to form three structural proteins [capsid (C), premembrane/membrane (prM/M) and envelope (E)] and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5) (Chambers et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Tyrosine 78 of premembrane protein is essential for assembly of West Nile virus

Tan

Bhuvanakantham

et al. 2009

Journal of General Virology

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Flavivirus premembrane (prM) protein plays an important role in conformational folding of the envelope (E) protein and protects it against premature fusion in acidic vesicles of the Golgi network. Currently, molecular determinants on the prM protein ectodomain which mediate critical steps during the flavivirus assembly process are poorly characterized. In this study, bioinformatics analysis and alanine scanning mutagenesis showed that the amino acid triplet valine 76, tyrosine 78 and glycine 79 is absolutely conserved among flavivirus prM ectodomains. Triple mutations engineered at these residues in prM ectodomain of West Nile virus (WNV) completely abrogated virus infectivity. Site-directed mutagenesis of prM protein revealed that tyrosine 78 of the amino acid triplet was required for virus infectivity and secretion. The mutation did not affect folding, post-translational modifications and trafficking of the prM and E proteins. Ultrastructural studies using transmission electron microscopy confirmed that virus particle formation was blocked by tyrosine 78 mutation. Specificity of assembly defect conferred by tyrosine 78 mutation was demonstrated by positive and negative trans complementation studies. Collectively, these results defined tyrosine 78 as a novel critical determinant present on prM protein ectodomain that is required for flavivirus assembly. Molecular dissection of prM protein function provides the crucial knowledge much needed in the elucidation of flavivirus particle formation.

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West Nile Virus–associated Flaccid Paralysis

Cited by 165 publications

References 26 publications

Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysis

Axonal transport mediates West Nile virus entry into the central nervous system and induces acute flaccid paralysis

West Nile virus meningoencephalitis

Tyrosine 78 of premembrane protein is essential for assembly of West Nile virus

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